Data from a one-patient study of an investigational siRNA-based treatment for the rare skin disorder pachyonychia congenita indicates the drug is safe and potentially effective, an official from the company developing the therapy told RNAi News last week.
However, because the route of administration, intradermal injections, proved more painful than anticipated, a planned follow-up trial will likely use an investigational cream-based delivery vehicle, TransDerm Founder and CEO Roger Kaspar said.
PC is a rare autosomal skin disorder caused by a mutation in any one of the dozens of genes encoding keratins. It is characterized by hypertrophic nail dystrophy and focal palmoplantar keraderma with blisters, and affects roughly 600 patients worldwide. There currently are no treatments available for PC.
In early 2008, TransDerm initiated a phase Ib trial of a naked, unmodified siRNA targeting a particular mutation associated with the disease (see RNAi News, 1/17/2008). The drug, dubbed TD101, was intradermally injected into a callus on the bottom of one foot of an adult PC patient, while a placebo injection was administered into a callus on the other foot
The trial, according to Kaspar, met its primary objective, with TD101 showing no signs of toxicity, but "we saw more efficacy than expected."
Measures of efficacy included a reduction in the size of calluses, the patient's responses to questions about the nature of the calluses on the treated and untreated feet, and a visual comparison of the treated foot to the untreated foot.
"After the study was unblinded so that we knew which [foot] was which, in the callous that was receiving the siRNA … half of [the site of injection] returned to normal, pink healthy skin that could be touched without pain," he said. "The patient said that, for the first time in her life, she could touch that area without any pain."
And while he cautioned against drawing any conclusions about TD101's efficacy from a one-patient study, Kaspar noted that "if you talk to the patient, [she] would tell you that something [therapeutic] was going on there."
Addressing the issue of immune responses triggered by siRNA, which has cast doubts over the apparent efficacy of therapies based on the small RNAs (see RNAi News, 9/5/2008), Kaspar noted that it is unlikely the effects observed with TD101 treatment were the result of, for example, toll-like receptor activation.
"Anything like that should make this disorder worse rather than better, unless we fundamentally are missing something," he said. "We've done some … studies with the siRNA and we don't see a whole lot of immunostimulatory activity. We can't rule that out 100 percent, but we're quite convinced that that's not an issue."
Further, the company has conducted experiments in a mouse model demonstrating that intradermal injections of naked, unmodified siRNA targeting green fluorescent protein result in specific inhibition of the GFP signal near the injection site, Kaspar said. He added that this work was recently accepted for publication.
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However, not every aspect of the phase Ib study's outcome was so positive, he said, noting that the intradermal injections proved more painful than anticipated.
There is "an incredibly painful blistering that happens with the keratodermis," Kaspar explained. "If you even get close to touching [affected areas, patients] began to flinch in anticipation of the pain they are going to have just by a slight touch.
"So we knew it was going to be painful … but it was more [so] than we expected," he said.
As a result, TransDerm expects that the next clinical study will examine TD101 when delivered topically using a lipid-based technology called gene cream, which is under development in collaboration with Stanford School of Medicine researcher Chris Contag.
The gene cream is essentially an alcohol/lipid formulation designed to transiently disrupt the stratum corneum so that an siRNA can cross into the epidermis and dermis, Kaspar said, although he declined to provide specific details about the technology.
In a study conducted at Stanford, gene cream containing the approved imaging agent indocyanin green was shown to penetrate both diseased pachyonychia congenital skin and callused skin from a healthy volunteer more readily than normal calf or forearm skin, and a three-month rabbit toxicology study revealed no adverse effects associated with the delivery vehicle.
TransDerm and its collaborators have also tested the gene cream in mice and found that it is able to deliver siRNAs to the target tissue, Kaspar said. However, the siRNA distribution is "spotty" and the functional activity of the siRNAs that have penetrated the stratum corneum has yet to be shown.
"That's what we're working on" now, he noted.
As for when that next human trial will commence, Kaspar said that the timing depends on whether TD101 will need to be modified for use with the gene cream.
"If we can show the functional knockdown with the unmodified siRNA in the cream, [another clinical trial] will happen quickly," he said. "If we have to modify the siRNA to increase the ability of the keratinocytes to take it up, then that modified siRNA becomes a whole new molecular entity in the eyes of the FDA," which would require the preparation and filing of a completely new investigational new drug application.
"That takes time and is unpredictable," he said.
'Patient-Friendly Delivery'
While its PC efforts progress, TransDerm is also advancing earlier-stage programs in other dermatologic indications where its various delivery technologies, including microneedle arrays, might be applicable.
"Right now, [we're working] to find patient-friendly delivery technologies because if we can solve that problem, there are lots of things that could be done," Kaspar said. He said that a previously disclosed program in epidermolysis bullosa simplex, a condition very similar to PC, remains ongoing.
However, he declined to comment in detail on the company's pipeline because "our focus is on PC. … We don't even really like to talk about other disorders because it distracts us from that immediate goal."
At the same time, TransDerm's work has attracted the attention of undisclosed industry partners interested in its delivery technologies. Kaspar confirmed that a number of alliances are in place, but said that confidentiality and disclosure agreements prevent him from discussing them.
But "the bottom line is we're always looking for people to help us," he added.